Modern people who live in the modern society, industrialized by the advance of science and civilization, experience decreased immunity and aging with gradual extension of life span, due to various stresses, pollution and spontaneous aging, etc. In particular, women experience physical and mental difficulties due to climacteric symptoms that start gradually in their forties.
Climacteric refers to a transition period in which physiological and sexual functions are reduced or lost due to the reduction of the female hormone, estrogen, resulting from the overall and gradual aging of ovarian functions, which is an endocrine syndrome. Climacteric symptoms include: symptoms due to vascular changes, such as facial flushing, tachycardia, sweating or headache, symptoms due to musculoskeletal changes, such as myalgia, arthralgia and back pain, symptoms due to urogenital changes, such as urinary frequency and urinary incontinence, and symptoms due to changes in the brain-nervous systems, such as memory loss, depression, loss of concentration, and dizziness. Other symptoms include macular degeneration and changes in skin and hair. Further, the hormonal changes may cause fatal diseases for women's health such as osteoporosis, cardiovascular diseases, and the like.
Therefore, there has been a need to develop a therapeutic agent capable of improving climacteric symptoms in order to improve the physical and mental health and the quality of life of middle-aged women. In order to improve these climacteric symptoms, drugs such as hormone replacement therapy and non-steroidal drugs have been developed. However, most of the drugs are known to have side effects such as headache and weight gain. Especially, it is known that estrogen replacement therapy may increase the risk of metrorrhagia, stroke, heart attack, breast cancer and uterine cancer, along with adverse reactions thereto, since the hormone is artificially administered into the body (Swaran L., et. al., Obstetrics & Gynecology, 91, 678-684, 1998).
Due to these problems, there is a growing interest in replacing estrogen therapy with natural methods of taking a food or an additive. Also, there is a need to develop a new climacteric remedy that has an excellent effect of alleviating climacteric symptoms without side effects.
Estrogen has a variety of biological functions including increasing cell numbers and cell differentiation. Estrogen exert its biological actions through two estrogen receptors, estrogen receptor-alpha (ER-α) and estrogen receptor-beta (ER-β), which belong to the nuclear receptor superfamily (Nilsson et al., 2001, Physiol. Rev., 81(4):1535-1565.). The action mechanism of the estrogen receptors (ERs) is that estrogen binds to intracellular estrogen receptors to form receptor dimers, which then bind to specific estrogen response elements (EREs) located in the promoter of the target gene to regulate the expression of the target gene. The two estrogen receptors have different tissue distribution patterns and ligand binding forces from each other, and this difference allows them to selectively play different roles as an agonist or an antagonist in different tissues (Kuiper et al., 1997, Endocrinology, 138(3):863-870.). Materials acting on estrogen receptors have been used as targets for developing hormone replacement therapy for menopausal women and chemotherapeutic agents for genital cancer. Therefore, relevant researches have been continuously conducted to find out natural products that activate estrogen receptors without side effects on the human body, because they could be useful for treatment and prevention of climacteric disorders.
Dendropanax morbifera LEV. is an evergreen broad-leaved forest tree belonging to the Araliaceae. It is a native tree species of Korea naturally growing in Jeju Island and the southwest coast area such as Wando, Bogildo Island and Haenam in Korea. The clove ingredient contained in Dendropanax morbifera LEV. includes a small amount of terpenes and a large amount of sesquiterpenes. It contains germacrene-d, β-selinene, α-amorphene, α-selinene, δ-cadinene, γ-cadinene, T-muurolol, β-elemene, bicyclo[4,4,0]dec-1-en-2-isopropyl-5-methyl-9-methylene, β-cadinene, germacrene-B, α-copaene, α-humulene, and α-cadinene, a small amount of linalool L, α-terpinene, α-cubebene, α-ylangene, (+)-calarene, 3,7-guaiadine, (−)-isoledene, β-cubebene, limonene, aromadendrene, and cadina-1,4-diene, etc., although there is a difference depending on the time and place of collection (Jeollanam-do, 1996). Meanwhile, literature records show that Dendropanax morbifera LEV. is effective for alcohol detoxification, treatment of an eye disease and jaundice, burn treatment, leprosy and is harmless to the human body (Li Shizen, Ben Cao Gang Mu (Compendium of Materia Medica), Munkwang Books of China, 1590). Also, it is known to exhibit sedative and tonic actions (Research on Unique Agricultural and Marine Products to be Globalized, section of Dendropanax morbifera LEV., Jeollanam-do, 1996). It is also known that the leaf extract fraction thereof has anticancer activity and a slightly weaker antioxidative action than α-tocopherol (Korean Patent Laid-Open No. 2000-0004499, Ho-Keun Park et al., 1998). However, the effect of Dendropanax morbifera LEV. on climacteric is not known at all.
Therefore, the present inventors have made efforts to develop a therapeutic agent for treating a climacteric disorder derived from a natural product and which is safe for the human body. As a result, the present inventors have found that extracts of Dendropanax morbifera LEV. exhibit a significant ER agonist activity within a cell, and exhibit a very potent ER agonist (full agonist) activity with an EC50 value of about 100 μg/ml. Thus, the present inventors have found that the extracts of Dendropanax morbifera LEV. comprising a high content of plant metabolites similar to estrogen can be useful as hormone replacement therapy capable of improving various symptoms derived from a deficiency of estrogen in menopausal women, and thereby completed the present invention.